Compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors) are likely to be useful in the treatment of diseases modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction and dependence, sexual dysfunction, shock, stroke, spinal damage and head trauma.
It is furthermore beneficial to obtain drugs that bind to opioid receptors which are not substrates of the enzyme CYP2D6. The presence of CYP2D6 enzyme among the human population is variable, and therefore it is easier to develop dosage schemes for a drug that are more generally applicable to a human population if the drug is not metabolized by CYP2D6.
Certain 4-arylpiperidine-based compounds are disclosed in European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents. 3-Azabicyclo[3.1.0]hexane derivatives useful as opioid receptor antagonists are also disclosed in WO 00/39089.
The synthesis, composition, and methods of use of certain 3-azabicyclo[3.1.0]hexane derivatives are disclosed in U.S. Pat. No. 6,313,312 and United States Patent Application 2003/0087898. The present invention provides an alternative route to these compounds with improved yield.
The aforementioned patents and patent applications are incorporated herein by reference therein in their entirety.